15-55432554-T-G

Variant names:

• chr15-55432554-T-G
• rs190788368
• NM_130810.4:c.1096A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_130810.4(DNAAF4):​c.1096A>C​(p.Met366Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M366V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAAF4 NM_130810.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• Publications: 0 publications found

Genes affected

DNAAF4 (HGNC:21493): (dynein axonemal assembly factor 4) This gene encodes a tetratricopeptide repeat domain-containing protein. The encoded protein interacts with estrogen receptors and the heat shock proteins, Hsp70 and Hsp90. An homologous protein in rat has been shown to function in neuronal migration in the developing neocortex. A chromosomal translocation involving this gene is associated with a susceptibility to developmental dyslexia. Mutations in this gene are associated with deficits in reading and spelling. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream cell cycle progression 1 (CCPG1) gene. [provided by RefSeq, Mar 2011]

DNAAF4-CCPG1 (HGNC:43019): (DNAAF4-CCPG1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring dyslexia susceptibility 1 candidate 1 (DYX1C1) and cell cycle progression 1 (CCPG1) genes on chromosome 15. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12551168).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130810.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF4	NM_130810.4	MANE Select	c.1096A>C	p.Met366Leu	missense	Exon 9 of 10	NP_570722.2
	DNAAF4-CCPG1	NR_037923.1		n.1351A>C		non_coding_transcript_exon	Exon 8 of 16
	DNAAF4	NM_001033560.2		c.1047+2351A>C		intron	N/A	NP_001028732.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF4	ENST00000321149.7	TSL:1 MANE Select	c.1096A>C	p.Met366Leu	missense	Exon 9 of 10	ENSP00000323275.3
	DNAAF4	ENST00000448430.6	TSL:1	c.1047+2351A>C		intron	N/A	ENSP00000403412.2
	DNAAF4	ENST00000457155.6	TSL:1	c.1048-1775A>C		intron	N/A	ENSP00000402640.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251424 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460600 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726572

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111136

Other (OTH) AF: 0.0000166 AC: 1 AN: 60316

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.75
DEOGEN2	Benign	0.00086	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.46		Loss of catalytic residue at M366 (P = 0.0232)
MVP		0.68
MPC		0.045
ClinPred		0.19	T
GERP RS		3.3
Varity_R		0.086
gMVP		0.31
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs190788368; hg19: chr15-55724752;